This invention relates to pyrazole derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes.
Reverse transcriptase is implicated in the infectious lifecycle of Human Immunodeficiency Virus (HIV). Compounds which interfere with the function of this enzyme have shown utility in the treatment of conditions caused by HIV and genetically related retroviruses, such as Acquired Immune Deficiency Syndrome (AIDS). There is a constant need to provide new and better modulators, especially inhibitors, of HIV reverse transcriptase, since the virus is able to mutate, becoming resistant to the effects of known modulators.
Antiviral activity is ascribed to a class of N(hydroxyethyl)pyrazole derivatives in U.S. Pat. No. 3,303,200. A number of pyrazoles are disclosed as reverse transcriptase inhibitors, including: a class of N-phenylpyrazoles (J. Med. Chem., 2000, 43, 1034); a class of C and S linked aryl pyrazoles (WO02/04424); and a class of O and S linked aryl pyrazoles, the O and S aryl link being adjacent to the nitrogen atom (WO02/30907).
According to the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein:
W—X—Y defines a five or six-membered partially saturated or aromatic ring containing 0 to 3 nitrogen atoms wherein X is CH or N and Y is CH or, when X is CH, may also be N; said ring being optionally substituted by halo, oxo, —CN, —COR5, —CONR5R5, —SO2NR5R5, —NR5SO2R5, —OR5, OR11, —NR5R5, —(C1-C6 alkylene)-NR5R5, R7, R11, or CF3;
R1 is C1-C6 alkylene;
R2 is H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, phenyl, benzyl, R8 or R9, said C1-C6 alkyl, C3-C7 cycloalkyl, phenyl and benzyl being optionally substituted by halo, —OR5, —OR10, —CN, —CO2R7, —OCONR5R5, —CONR5R5, —C(═NR5)NR5OR5, —CONR5NR5R5, —NR6R6, —NR5R10, —NR5COR5, —NR5COR8, —NR5COR10, —NR5CO2R5, —NR5CONR5R5, —SO2NR5R5, —NR5SO2R5, —NR5SO2NR5R5, R8 or R9;
R3 is H, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, benzyl, halo, —CN, —OR7, —CO2R5, —CONR5R5, R8 or R9, said C1-C6 alkyl, C3-C7 cycloalkyl, phenyl and benzyl being optionally substituted by halo, —CN, —OR5, —CO2R5, —CONR5R5, —OCONR5R5, —NR5CO2R5, —NR6R6, —NR5COR5, —SO2NR5R5, —NR5CONR5R5, —NR5SO2R5, R8 or R9;
R4 is phenyl, naphthyl or pyridyl, each being optionally substituted by R8, halo, —CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, —CONR5R5, OR11, SoxR6, O—(C1-C6 alkylene)-CONR5R5, O—(C1-C6 alkylene)-NR5R5, or O—(C1-C6 alkylene)—OR6;
each R5 is independently either H, C1-C6 alkyl or C3-C7 cycloalkyl or, when two R5 groups are attached to the same nitrogen atom, those two groups taken together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl or morpholinyl, said azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl and morpholinyl being optionally substituted by C1-C6 alkyl or C3-C7 cycloalkyl;
each R6 is independently either H, C1-C6 alkyl or C3-C7 cycloalkyl;
R7 is C1-C6 alkyl or C3-C7 cycloalkyl;
R8 is a five or six-membered, aromatic heterocyclic group containing (i) from 1 to 4 nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen heteroatom(s) and 1 oxygen or 1 sulphur heteroatom or (iii) 1 or 2 oxygen or sulphur heteroatom(s), said heterocyclic group being optionally substituted by halo, oxo, —CN, —COR5, —CONR5R5, —SO2NR5R5, —NR5SO2R5, —OR5, —NR5R5, —(C1-C6 alkylene)-NR5R5, C1-C6 alkyl, fluoro(C1-C6)alkyl or C3-C7 cycloalkyl;
R9 is a four to seven-membered, saturated or partially unsaturated heterocyclic group containing (i) 1 or 2 nitrogen heteroatom(s) or (ii) 1 nitrogen heteroatom and 1 oxygen or 1 sulphur heteroatom or (iii) 1 oxygen or sulphur heteroatom, said heterocyclic group being optionally substituted by oxo, C1-C6 alkyl, C3-C7 cycloalkyl, —SO2R5, —CONR5R5, —COOR5, —CO—(C1-C6 alkylene)-OR5 or —COR5 and optionally substituted on a carbon atom which is not adjacent to a heteroatom by halo, —OR5, —NR5R5, —NR5COR5, —NR5COOR5, —NR5CONR5R5, —NR5SO2R5 or —CN;
R10 is C1-C6 alkyl substituted by R8, R9, —OR5, —CONR5R5, —NR5COR5 or —NR5R5;
R11 is phenyl optionally substituted by halo, —CN, —COR5, —CONR5R5, —SO2NR5R5, —NR5SO2R5, —OR5, —NR5R5, —(C1-C6 alkylene)-NR5R5, C1-C6 alkyl, halo(C1-C6)alkyl or C3-C7 cycloalkyl; and
x and n are independently 0, 1 or 2.
In the above definitions, halo means fluoro, chloro, bromo or iodo. Unless otherwise stated, alkyl, alkenyl, alkynyl, alkylene and alkoxy groups containing the requisite number of carbon atoms can be unbranched or branched chain. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkenyl include ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methylpropen-1-yl or 2-methylpropen-3-yl. Examples of alkynyl include ethynyl, propyn-1-yl, propyn-3-yl, 1-butyn-1-yl, 1-butyn-3-yl, 1-butyn4-yl, 2-butyn-1-yl. Examples of alkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene and 1,3-propylene. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Where a heterocyclic group R8 or R9 is attached to an oxygen, sulphur or nitrogen heteroatom the heterocyclic group R8 or R9 must be linked through a ring carbon atom.
The pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and the base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, chloride, bromide, iodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, fumarate, pamoate, aspartate, besylate, carbonate, bicarbonate/, camsylate, D and L-lactate, D and L-tartrate, esylate, mesylate, malonate, orotate, gluceptate, methylsulphate, stearate, glucuronate, 2-napsylate, tosylate, hibenzate, nicotinate, isethionate, malate, maleate, citrate, gluconate, succinate, saccharate, benzoate, esylate, and pamoate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc, choline, diolamine, olamine, arginine, glycine, tromethamine, benzathine, lysine, meglumine and diethylamine salts.
For reviews on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19, 1977 and Bighley et al, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York, 1996, Vol 13, pp453-497
The pharmaceutically acceptable solvates of the compounds of formula (I) include the hydrates thereof.
The compound of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compound. Examples of such derivatives are described in: Drugs of Today, Volume 19, Number 9, 1983, pp 499-538; Topics in Chemistry, Chapter 31, pp 306-316; and in “Design of Prodrugs” by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference) and include: esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, sulphonamides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.
The invention encompasses all isomers of the compound of formula (I) and pharmaceutically acceptable salts, solvates or derivatives thereof, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures).
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or high performance liquid chromatography (HPLC) of a stereoisomeric mixture of compounds. An individual enantiomer of a compound may also be prepared from a corresponding optically pure intermediate or by resolution, such as by HPLC of the corresponding racemate using a suitable chiral support, or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
The compound of formula (I) and pharmaceutically acceptable salts, solvates or derivatives thereof may have the ability to crystallize in more than one form, a characteristic known as polymorphism, and all such polymorphic forms (“polymorphs”) are encompassed within the scope of the invention. Polymorphism generally can occur as a response to changes in temperature or pressure or both, and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics, and typically the x-ray diffraction patterns, solubility behaviour, and melting point of the compound are used to distinguish polymorphs.
Compounds of formula (I), pharmaceutically acceptable salts, solvates and derivatives thereof, isomers thereof, and polymorphs thereof, are hereinafter referred to as the compounds of the invention.
Preferred compounds of the invention are the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof.
Preferably, W—X—Y defines a five or six-membered partially saturated or aromatic ring containing 0 to 2 nitrogen atoms wherein X is CH or N and Y is CH or, when X is CH, may also be N; said ring being optionally substituted by halo, oxo, —CN, —OR5, —NR5R5, —(C1-C6 alkylene)-NR5R5, R7, or CF3.
Preferably, W—X—Y defines a five or six-membered partially saturated or aromatic ring containing 0 to 2 nitrogen atoms wherein X is CH or N and Y is CH or, when X is CH, may also be N; said ring being optionally substituted by oxo, —CN, —C1-C6 alkoxy, —NH2, —N(C1-C6 alkyl)(C1-C6 alkyl), C1-C6 alkyl, or CF3.
Preferably, W—X—Y defines a phenyl or pyridyl ring, and said ring being optionally substituted by —CN.
Preferably, R1 is methylene, ethylene or propylene.
Preferably, R1 is methylene.
Preferably, R2 is H, C1-C6 alkyl, C3-C6 alkenyl, phenyl, benzyl or R9, said phenyl, benzyl or C1-C6 alkyl being optionally substituted by halo, —OR5, —OR10, —CN, —CO2R7, —OCONR5R5, —CONR5R5, —C(═NR5)NR5OR5, —CONR5NR5R5, —NR6R6, —NR5R12, —NR5COR5, —NR5COR8, —NR5COR12, —NR5CO2R5, —NR5CONR5R5, —SO2NR5R5, —NR5SO2R5, R8 or R9.
Preferably, R2 is H, C1-C6 alkyl, phenyl or benzyl, said C1-C6 alkyl being optionally substituted by halo, —OR5, —OR10 or —CN.
Preferably, R2 is H or C1-C3 alkyl.
Preferably, R2 is H.
Preferably, R3 is H, C1-C6 alkyl or C3-C7 cycloalkyl, said C1-C6 alkyl being optionally substituted by halo, —CN, —OR5, —CO2R5, —CONR5R5, —OCONR5R5, —NR5CO2R5, —NR6R6, —NR5COR5, —SO2NR5R5, —NR5CONR5R5, —NR5SO2R5, R8 or R9.
Preferably, R3 is H or C1-C6 alkyl.
Preferably, R3 is H or C1-C4 alkyl.
Preferably, R3 is methyl or ethyl.
Preferably, R4 is phenyl optionally substituted by R8, halo, —CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl or C1-C6 alkoxy.
Preferably, R4 is phenyl substituted by R8, halo, —CN, C1-C6 alkyl, or C1-C6 alkoxy.
Preferably, R4 is phenyl substituted by halo or —CN.
Preferably, R4 is phenyl substituted by chloro or —CN.
Preferably, R4 is 3,5-dicyanophenyl or 3-chloro-5-cyanophenyl.
Preferably, R8 is pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each being optionally substituted by halo, —CN, —COR5, —CONR5R5, —SO2NR5R5, —NR5SO2R5, —OR5, —NR5R5, —(C1-C6 alkylene)-NR5R5, —(C1-C6 alkyl, fluoro(C1-C6)alkyl or C3-C7 cycloalkyl.
Preferably, R8 is imidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrazinyl or pyrimidinyl, each being optionally substituted by halo, —CN, —COR5, —CONR5R5, —SO2NR5R5, —NR5SO2R5, —OR5, —NR5R5, —(C1-C6 alkylene)-NR5R5, C1C6 alkyl, fluoro(C1-C6)alkyl or C3-C7 cycloalkyl.
Preferably, R8 is imidazolyl, pyrazolyl, 1,2,4-trazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrazinyl or pyrimidinyl, each being optionally substituted by —OR5, —NR5R5 or C1-C6 alkyl.
Preferably, R8 is imidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrazinyl or pyrimidinyl, each being optionally substituted by —OH, —NH2 or methyl.
Preferably, R9 is azetidinyl, tetrahydropyrrolyl, piperidinyl, azepinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepinyl, morpholinyl, piperazinyl or diazepinyl, each being optionally substituted by oxo, C1-C6 alkyl, C3-C7 cycloalkyl, —SO2R5, —CONR5R5, —COOR5, —CO—(C1-C6 alkylene)-OR5 or —COR5 and optionally substituted on a carbon atom which is not adjacent to a heteroatom by halo, —OR5, —NR5R5, —NR5COR5, —NR5COOR5, —NR5CONR5R5, —NR5SO2R5 or —CN.
Preferably, R9 is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl or morpholinyl, each being optionally substituted by oxo, C1-C6 alkyl, C3-C7 cycloalkyl, —SO2R5, —CONR5R5, —COOR5, —CO—(C1-C6 alkylene)-OR5 or —COR5 and optionally substituted on a carbon atom which is not adjacent to a heteroatom by halo, —OR5, —NR5R5, —NR5COR5, —NR5COOR5, —NR5CONR5R5, —NR5SO2R5 or —CN.
Preferably, R9 is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl or morpholinyl, each being optionally substituted by C1-C6 alkyl, —SO2R5, —CONR5R5, —COOR5, —CO—(C1-C6 alkylene)-OR5 or —COR5 and optionally substituted on a carbon atom which is not adjacent to a heteroatom by —OR5 or —NR5COR5.
Preferably, R9 is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl or morpholinyl, each being optionally substituted by —CH3, —SO2CH3, —CONH2, —COOCH3, —COCH2OCH3 or —COCH3 and optionally substituted on a carbon atom which is not adjacent to a heteroatom by —OCH3 or —NHCOCH3.
Preferably, R10 is C1-C4 alkyl substituted by R8, R9, —OR5, —CONR5R5, —NR5COR5 or —NR5R5.
Preferably, R10 is C1-C4 alkyl substituted by R9, —OR5, —NR5COR5 or —NR5R5.
Preferably, R10 is C1-C2 alkyl substituted by tetrahydrofuranyl, —OCH3, —NHCOCH3 or —NH2.
Preferably, R11 is phenyl substituted by halo, —CN, —COR5, —CONR5R5, —SO2NR5R5, —NR5SO2R5, —OR5, —NR5R5, —(C1-C6 alkylene)-NR5R5, C1-C6 alkyl, halo(C1-C6)alkyl or C3-C7 cycloalkyl.
Preferably, R11 is phenyl substituted by halo, —CN, —CONR5R5, —SO2NR5R5 or —OR5.
Preferably, R11 is phenyl substituted by fluoro, —CN, —CONH2, —SO2NH2 or —OCH3.
Preferably, n is 0 or 1.
Preferably, n is 0.
Preferred groups of compounds according to the invention include all combinations of the preferred definitions for individual substituents given above.
Preferred compounds of the invention are:
3-chloro-5-[3-methyl-5-(1-oxo-1,3-dihydro-isoindol-2ylmethyl)-1H-pyrazol-4-yloxy]-benzonitrile;
5-[3-methyl-5-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-1H-pyrazol-4-yloxy]-isophthalonitrile;
and pharmaceutically acceptable salts, solvates or derivatives thereof.
The compounds of the invention may have advantages over those of the prior art with regard to a number of useful properties or combinations thereof, such as potency, duration of action, pharmacokinetics, spectrum of activity, side effect profile, solubility, chemical stability, and so on.
The compounds of the invention may be prepared by any method known in the art for the preparation of compounds of analogous structure. The compounds of the invention can be prepared by the procedures described in the methods below, or by the specific methods described in the Examples, or by similar methods to either. The invention also encompasses any one or more of these processes for preparing the compounds of the invention, in addition to any novel intermediates used therein.
In the following methods, W, X, Y, R1 to R4, and n are as previously defined for a compound of formula (I), unless otherwise stated; Z is H or C1-C4 alkoxy (e.g. methoxy); THF is tetrahydrofuran; DCM is dichloromethane; DMF is N,N-dimethylformamide and Ac is acyl.
Compounds of formula (I) may be prepared according to Scheme 1 that follows.
According to Scheme 1, compounds of formula (I) may be prepared by the reaction of a compound of formula (II) with an amine of formula (IV) under conventional conditions. For aldehydes of formula (II), i.e. wherein Z is H, reaction conditions are those of reductive amination/alkylation in the presence of a reducing agent. For esters of formula (II), i.e. wherein Z is C1-C4 alkoxy (e.g. methoxy), reaction conditions are those of alkylation/condensation in the presence of a base. 
Conveniently, reductive amination/alkylation is effected using a hydride reducing agent, such as a borohydride (e.g. Na(OAc)3BH or NaCNBH3); optionally, an activating agent, such as acetic acid or sodium acetate; in the presence of a solvent, such as an ether (e.g. THF) or a haloalkane (e.g. DCM); and at ambient to elevated temperature, such as ambient temperature.
Conveniently, alkylation/condensation is effected using an alkali metal base, such as an alkali metal carbonate (e.g. sodium, potassium or caesium carbonate); in the presence of a solvent, such as a polar aprotic solvent (e.g. acetonitrile or DMF); and at ambient to elevated temperature, such as ambient temperature to 40° C.
Amines of formula (IV) may be prepared by reaction of the corresponding halide of formula (V) with a source of ammonia under conventional conditions. Conveniently the reaction is effected in the presence a solvent, such as an alcohol (e.g. ethanol or isopropanol), said solvent being saturated with ammonia; and at reduced to ambient to elevated temperature, such as reduced temperature (e.g. 0° C.).
Compounds of formula (V) may be prepared by halogenation of a compound of formula (VI) using a source of halogen, such as a molecular halogen (e.g. bromine) or an N-halo-succinimide (e.g. N-bromo-succinimide), under conventional conditions. Conveniently the halogenation is effected in the presence of a solvent, such as a haloalkane (e.g. carbon tetrachloride or 1,1,1-trichloroethane); optionally a radical initiation catalyst, such as ultraviolet light or AIBN; and at ambient to elevated temperature, such as under reflux.
Compounds of formula (VI) may be prepared by the reaction of a compound of formula (VIII) with a hydrazine of formula (VII), or a salt or hydrate thereof. Conveniently, the reaction is effected a solvent, such as a protic solvent (e.g. acetic acid); at ambient to elevated temperature, such as ambient temperature; and optionally in the presence of an acid (e.g. acetic acid) or a base, such as a tertiary amine (e.g. triethylamine).
Compounds of formula (VIII) may be prepared by the reaction of a compound of formula (X) with an alcohol of formula (IX). Conveniently, the reaction is effected in the presence of a solvent, such as a polar solvent (e.g. acetone); a base, such as an inorganic base, preferably a metal carbonate (e.g. potassium or caesium carbonate); optionally, a nucleophilic catalyst, such as sodium iodide or tetrabutylammonium iodide; and at ambient to elevated temperature, such as elevated temperature (e.g. under reflux).
Ketoesters of formula (IX) are either commercially available, known in the literature, or may be prepared by conventional methods (e.g., where Lg1 is Cl, by the chlorination of corresponding ketoesters, for instance using sulphonyl chloride).
Compounds of formula (I) may also be prepared by reaction of a compound of formula (III) with an amine of formula (IV) under conventional conditions. Conveniently, the reaction is effected in the presence of a reducing agent under conditions of reductive amination/alkylation, such as those described above for the preparation of a compound of formula (I) by reaction of a compound of formula (II) with an amine of formula (IV).
Compounds of formula (I) in which R3 is halo can be prepared from a compound of formula (XI) under conventional conditions. Conveniently, the reaction is effected by an inorganic acid halide, such as an inorganic acid chloride (e.g. POCl3); optionally in the presence of a solvent, such as a polar aprotic solvent (e.g. N,N-dimethylformamide); and at reduced to ambient temperature, such as ambient temperature.
Compounds of formula (XI) may be prepared using the routes described above, mutatis mutandis.
It will be appreciated by those skilled in the art that, in many cases, compounds of formula (I) may be converted into other compounds of formula (I) by functional group transformations, including for example the following interconversions.
Compounds of formula (I) in which R2 is optionally substituted C1-C6 alkyl may be prepared from compounds of formula (I) in R2 is H by reaction with an alkylating agent. Suitable alkylating agents include bromoacetonitrile, ethyl 4-chloroacetoacetate, methyl bromoacetate and chloroethylamine hydrochloride. Conveniently, alkylation is effected in the presence of a suitable solvent, such as an alcohol (e.g. ethanol) or a polar aprotic solvent (e.g. N,N-dimethylformamide); a base, such as a metal hydride (e.g. sodium hydride) or metal alkoxide (e.g. sodium ethoxide); and at ambient to elevated temperature, such as under reflux.
Compounds of formula (I) in which R2 or R3 contains a hydroxy group may be prepared from the corresponding compound of formula (I) in which R2 or R3 contains an ester group by reduction. Conveniently, the reduction is effected by a metal hydride agent, such as lithium aluminium hydride; in a solvent, such as an ether (e.g. diethyl ether); and at reduced temperature, such as from −78° C. to 0° C.
Compounds of formula (I) in which R2 or R3 are substituted by a heterocycle of formula R8 and R9 may be prepared by standard heterocycle-forming reactions well known to the skilled man (see, for example, Advanced Organic Chemistry, 3rd Edition, by Gerry March or Comprehensive Heterocyclic Chemistry, A. R. Katritzky, C. W. Rees, E. F. V. Scriven, Volumes 1-11).
Compounds of formula (I) in which R3 is —CO2H may be prepared by hydrolysis of a corresponding compound of formula (I) in which R3 is —CO2R5. Conveniently, the reaction is effected in the presence of a solvent, such as an alcohol (e.g. aqueous ethanol), or an ether (e.g. aqueous 1,4-dioxan); and in the presence of a base, such as a metal hydroxide (e.g. sodium hydroxide). The skilled artisan will appreciate that such an acid may be converted into a primary amide by reaction with ammonia and a suitable coupling agent, such as a carbodiimide, e.g. dicyclohexylcarbodiimide, and that such a primary amide may then be converted into a nitrile by dehydration with a suitable dehydrating agent, such as phosphoryl chloride.
Compounds of formula (I) in which R3 is C1-C6 alkyl may be converted into the compounds of formula (I) in which R3 is C1-C6 alkyl substituted by halo (such as bromo), by halogenation, using a suitable halogenating agent. Conveniently the reaction is effected in the presence of a solvent, such as a haloalkane (e.g. dichloromethane) and at ambient temperature. Suitable halogenating agents include halogens (e.g. bromine) or N-halosuccinimides (e.g. N-bromsuccinimide).
Compounds of formula (I) containing an —OH, —NH— or —NH2 group may be prepared by the deprotection of the corresponding compound bearing an —OP1, —NP1- or —NHP1 group, respectively, wherein the group P1 is a suitable protecting group. Examples of suitable protecting groups will be apparent to the skilled person; see, for instance, ‘Protecting groups in Organic Synthesis (Second Edition)’ by Theodora W. Green and Peter G. M. Wuts, 1991, John Wiley and Sons. Such compounds bearing an —OP1, —NP1- or —NHP1 group may be prepared using the routes described above, mutatis mutandis.
Compounds of formulae (II), (III), (VII) and (IX) are either commercially available, known in the literature or easily prepared by methods well known to those skilled in the art, such as those described in the Preparations hereinafter.
The compounds of the invention can be administered alone, but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, the compounds of the invention can be administered orally, buccally or sublingually in the form of tablets, capsules, multi-particulates, gels, films, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications. The compounds of the invention may also be administered as fast-dispersing or fast-dissolving dosage forms or in the form of a high energy dispersion or as coated particles. Suitable formulations of the compounds of the invention may be in coated or uncoated form, as desired.
Such solid pharmaceutical compositions, for example, tablets, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.